Neuronal hyperexcitability contributes to the cognitive defects in Alzheimer's Dementia (AD). However, the mechanisms underlying neuronal hyperexcitability are not well understood. Development of AD is also preceded by decrease in neuronal metabolism. Hypometabolism in AD is associated with downregulation of enzymes important in energy homeostasis, among which is the hypoxia-sensitive enzyme Glycerol-3-phosphate dehydrogenase-like-1 (Gpdl1) which has an important place in the nicotinamide adenine dinucleotide (NAD+) metabolome in cells. However, the integrative cellular/molecular mechanisms linking change in NAD+ metabolome to neuronal excitability are also poorly understood. Our prior work has shown the role of the NAD+-dependent Sirtuin1 lysine deacetylase regulates acetylation and properties of the cardiac voltage-gated sodium channel Nav1.5. Moreover, we preliminary data in the parent grant shows that Gpd1L governs Nav1.5. Based on this work, the parent grant proposes to determine how the interaction between Gpd1l, Sirtuin1 and the NAD+ metabolome regulates the cardiac sodium channel and cardiac electrical activity In this supplement we will apply this approach to investigate the role of Gpd1l, Sirtuin1 and the NAD+ metabolome in regulation of the neuronal voltage-gated sodium channel (Nav1.6). Nav1.6 is a close homolog of Nav1.5 and is integral to neuronal excitation. ?-amyloid (A?) peptides which play a causal role in Alzheimer's dementia, stimulate Nav1.6 expression and activity. Because voltage-gated sodium channels are highly conserved and have significant homology in key regulatory residues and domains, we hypothesize that Gpd1l, Sirtuin1 and the NAD+ metabolome interact to affect Nav1.6 expression and function, similar to their effect on Nav1.5, and thus play a part in modulating neuronal excitability. The application will use state-of-the-art electrophysiological methodologies, as well as novel reagents we have generated for the parent grant, including genetically modified Gpd1l and Sirt1 mice, reagents to manipulate the NAD+ metabolome, and custom antibody toward acetylated voltage-gated sodium channels. Thus, this application falls within the scope of the parent grant. It will explore whether the Gpd1l-Sirtuin1-NAD+ interactome can modulate neuronal excitability in the context of ?-amyloid toxicity through their impact on the post-translational landscape, surface expression, and conductance properties of Nav1.6. These studies will open a new chapter in understanding the metabolo-molecular basis of neuronal sodium channel excitability, dysregulation of which plays a vital role in cognitive impairment of AD.